4-bromo-3, 11-diketo-17(alpha)-hydroxy-20-acyloxypregnanes and process



Patented May 2, 1950 UNITED S A E PATENT QFFlCEl-BROMO-3,11-DIKETO-17(c)HYDBOXY-20e ACYLOXYPREGNANES Ann rltooess Lewisll. Sarett, Princeton, N. J fi sig or to Merck & 00., Inc., Railway, N.3., a corporation of New Jersey N Drawing. Application June 1, 1946,

Serial No. 6' 73,890

6 Claims. (Cl. ESQ-+3914) 1 2 'I 'his invention is concerned generallywith stereochemical configuration of which is identical novel chemicalcompounds of the cyclop'entanowith that of the naturally occurringadrenal dimethyl polyhydrophenanthrene series and hormones, isparenthetically designated a. The processes of preparing the same; moreparticuepimeric configuration is designated In the larly it relatestostereoisomers of i-bromo-3, 1lstructural formula, the formerconfiguration is diketo-17-hydroxy-2O acyloxy pregnaneand with shown bywriting the C17 fsubstituent (hydroxyl) methods of manufacturing thesecompounds to the right of the C17 carbon side chain thus:

from readily available starting material. The new compounds thusproduced are of value in the reparation of hormones showing an and iactiv uqhasad n te q They )YOH are a s Q v lue m a s ,of e blish n thstructure of other 'qrganic compounds.

These stereoisomei'ic fi-bromo-ifll-diketod'lhydroxy-- acyloxy pregnanescan be represented by the following structural formula:

in the latter case above the side chain thus:

H 5 ween-9e In accordance with the present invention, it

3 3; is now found that stereoisbmers of 4-1310111193-1311- zoonon k-hydroxy-20-acyl xy pre nane" can be 3 8 1 a synthesized by reactionsdesignated generically aOOH s40 H /12 17 as follows. o=011 13 con, OH: H,18 14 15 A s e H202 310 80H OH; OHOR on A B J 3 5 7 Hz fil \g/Brominating :lBr H H2 (1) ,aget

in the abbreviated form:

CH3 OH:

*HOR OH wherein R has the significance above defined. In theaboyeformulae, 3 isan acyl radical.

In the following description of the intention, The reactions indicatedabdye are "conducted the stereochemicalrelationships of thesubasfo'llowsz The starting "material, a stereoisomer ituents areindicated by the following convenof 3,11-diketo-17-hydroxy-20-acyloxypregnane tion: (1), which is prepared according to processes (1) Thestereochemical relationships of rings disclosed in my co-pendingapplications, Serial A and B is indicated in the formula by a solid No.605,194, filed July 14, 1945, now abandoned; line representing thevalence bond in the cis Serial No. 687,982, filed August 2, 1946; andSerial configuration. No. 683,427, filed July 13, 1946, now Pat. No.

(2) A substituent in the Cr: position, the 2,493,780, is reacted with abrominating agent to produce the corresponding stereoisomer of 4 bromo3,11 diketo-17-hydroxy-20-acyloxy pregnane (2).

In carrying out the presently invented process, a stereoisomer of3,11-diketo-17-hydroxy-20- acyloxy pregnane as, for example,3,11-diketo-1'7- (a)-hydroxy-20acetoxy pregnane; 3,11-diketo- 17-(a)-hydroxy-20-propionoxy pregnane; 3,11- diketo-17 (a) -hydroxy 20butyroxy-pregnane; 3,11-diktO-17-(a) -hydroxy 20 benzoxy pregnane;3,11-diketo 17 (,8) -hydroxy-20-acetoxy pregnane or mixtures thereof, isreacted with a substantially equimolecular quantity of bromine and aninert solvent such as glacial acetic acid, the bromine entering themolecule at the 4- position to form the corresponding 4-bromo-3,l1-diketo-17-hydroxy-20-acyloxy pregnane, which can be represented by thefollowing structural formula:

wherein R is acyl and X is halogen.

It is important not to use substantially more than an equimolecularquantity of halogen because an excess favors the formation of thedihalide.

In applicants preferred procedure, wherein the 3,11dlktO-17(a)-hydroxy-20-acyloxy pregnane is reacted with bromine in glacial aceticacid, the product is isolated as follows: The reaction product isdissolved in a water-immiscible solvent, such as ether, the solventextract washed with a dilute alkaline aqueous solution containing analkali or alkaline earth hydroxide or carbonate, whereby acidicmaterials are removed from the solvent layer which is separated andevaporated to dryness under reduced pressure. The product thus obtainedis further purified, if desired, by recrystallization from an aliphaticalcohol, such as ethyl alcohol, to produce the corresponding4-bromo-3,11-diketo- 1'7 (cz) -hydroxy- ZO-acyloxy pregnane.

The 'following examples illustrate methods of carrying out the presentinvention, but it is to be understood that these examples are given byway of illustration and not of limitation.

Example I About 860 mg. of 3,11-diketo-17-(a)-hydr0xyso ZO-acetoxypregnane is dissolved in a mixture of about 3 cc. of acetic acid andabout 3 cc. of chloroform and a solution containing about 370 mg. ofbromine in about 3 cc. of acetic acid is added thereto. The mixture isallowed to stand until a the reaction is substantially complete asindicated by decolorization of the solution, and the mixture is pouredinto a mixture of water and chloroform. The chloroform layer isseparated and washed with dilute aqueous sodium bicarbonate solution,then with water and finall evaporated to dryness under reduced pressure.The residual material is recrystallized from ethyl alcohol to producesubstantially pure 4-bromo-3,11-diketo-17-(a)- hydroxy-20-acetoxypregnane; M. P. ISO- C. (with loss of alcohol of crystallization).

Example I] About 1 molecular equivalent of 3,11-diketo-17- (oz)-hydroxy-20-propionoxy pregnane is dissolved in a propionicacid-ethylene dichloride solution and reacted with about 1 molecularequivalent of bromine and the product isolated substantially asdescribed in Example 1. After recrystallization from methyl alcohol,there is obtained the corresponding 4-brom03,11 diketo-l'? (a)-hydroxy-20-propionoxy pregnane.

Various changes and modifications may be made in my invention asdescribed without departing from the spirit and scope thereof. To theextent that these changes and modifications are within the purview ofthe annexed claims, they are to be considered as part of my invention.

I claim:

1. The process of preparing 4-bromo-3,11- diketo-17-(a) -hydroXyZO-acyloxy pregnanes which comprises reacting together substantiallyequimolecular proportions of bromine and a 20- substituted 3,1l-diketo-l'l- (a) -hydroxy-pregnane, in which the substituent in the20-position is a radical selected from the class which consists ofbenzoyloxy and lower aliphatic carboxylic acyloxy radicals.

2. The process which comprises reacting 3,11- diketo-l'l- (or)-hydroxy-20-acetoxy pregnane with a substantially equimolecularproportion of bromine to produce 4-bromo-3,11-dil eto-l7-(a)-hydroxy-ZO-acetoxy pregnane.

3. The process which comprises reacting 3,11- diketo 17-(a)-hydroxy-20-propionoxy pregnane with a substantially equimolecularproportion of bromine to produce 4-brom0-3,11-diketo-17-(a)-hydroxy-ZO-propionoxy pregnane.

4. 20-substituted 4-bromo-3,l1 diketo-ll-(whydroxy-pregnanes in whichthe substituent in the 20-position is a lower aliphatic carboxylicacyloxy radical.

5. 4-bromo-3,11-diketo 17-(a)-hydroxy-20- acetoxy-pregnane.

6. 4-bromo-3,11-diketo 17-(a)-hydroxy 20- propionoxy pregnane.

' LEWIS H. SARETT.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,153,700 Serini Apr. 11, 19392,232,730 Reichstein Feb. 25, 1941 2,256,500 Serini Sept. 23, 19412,345,711 Marker Apr. 4, 1944 2,403,683 Reichstein July 9, 1946

1. THE PROCESS OF PREPARING 4-BROMO-3,11DIKETO-17-(A)-HYDROXY -20-ACYLOXY - PREGNANES WHICH COMPRISES REACTING TOGETHER SUBSTANTIALLYEQUIMOLECULAR PROPORTIONS OF BROMINE AND A 20SUBSTITUTED3,11-DIKETO-17-(A)-HYDROXY-PREGNANE, IN WHICH THE SUBSTITUENT IN THE20-POSITION IS A RADICAL SELECTED FROM THE CLASS WHICH CONSISTS OFBENZOYLOXY AND LOWER ALIPHATIC CARBOXYLIC ACYLOXY RADICALS.